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PLoS Genetics

Nicholas A Willis, Arvind Panday, Erin E Duffey, Ralph Scully
Classical non-homologous end joining (C-NHEJ) and homologous recombination (HR) compete to repair mammalian chromosomal double strand breaks (DSBs). However, C-NHEJ has no impact on HR induced by DNA nicking enzymes. In this case, the replication fork is thought to convert the DNA nick into a one-ended DSB, which lacks a readily available partner for C-NHEJ. Whether C-NHEJ competes with HR at a non-enzymatic mammalian replication fork barrier (RFB) remains unknown. We previously showed that conservative "short tract" gene conversion (STGC) induced by a chromosomal Tus/Ter RFB is a product of bidirectional replication fork stalling...
July 19, 2018: PLoS Genetics
Arantxa Rosado, Teresa Cordero, Guillermo Rodrigo
Synthetic biology aims at (re-)programming living cells like computers to perform new functions for a variety of applications. Initial work rested on transcription factors, but regulatory RNAs have recently gained much attention due to their high programmability. However, functional circuits mainly implemented with regulatory RNAs are quite limited. Here, we report the engineering of a fundamental arithmetic logic unit based on de novo riboregulation to sum two bits of information encoded in molecular concentrations...
July 19, 2018: PLoS Genetics
Lincoln T Lewerke, Paige J Kies, Ute Müh, Craig D Ellermeier
Extra Cytoplasmic Function (ECF) σ factors are a diverse group of alternate σ factors bacteria use to respond to changes in the environment. The Bacillus subtilis ECF σ factor σV responds to lysozyme. In the absence of lysozyme, σV is held inactive by the anti-σ factor, RsiV. In the presence of lysozyme RsiV is degraded via regulated intramembrane proteolysis, which results in the release of σV and thus activation of lysozyme resistance genes. Signal peptidase is required to initiate degradation of RsiV...
July 18, 2018: PLoS Genetics
Hans M Dalton, Sean P Curran
Across organisms, manipulation of biosynthetic capacity arrests development early in life, but can increase health- and lifespan post-developmentally. Here we demonstrate that this developmental arrest is not sickness but rather a regulated survival program responding to reduced cellular performance. We inhibited protein synthesis by reducing ribosome biogenesis (rps-11/RPS11 RNAi), translation initiation (ifg-1/EIF3G mutation and egl-45/EIF3A RNAi), or ribosome progression (cycloheximide treatment), all of which result in a specific arrest at larval stage 2 of C...
July 18, 2018: PLoS Genetics
Norah Owiti, Shanqiao Wei, Ashok Bhagwat, Nayun Kim
Recombination and mutagenesis are elevated by active transcription. The correlation between transcription and genome instability is largely explained by the topological and structural changes in DNA and the associated physical obstacles generated by the transcription machinery. However, such explanation does not directly account for the unique types of mutations originating from the non-canonical residues, uracil or ribonucleotide, which are also elevated at highly transcribed regions. Based on the previous findings that abasic (AP) lesions derived from the uracil residues incorporated into DNA in place of thymine constitute a major component of the transcription-associated mutations in yeast, we formed the hypothesis that DNA synthesis ensuing from the repair of the transcription-induced DNA damage provide the opportunity for uracil-incorporation...
July 17, 2018: PLoS Genetics
Yu Jiang, Sai Chen, Daniel McGuire, Fang Chen, Mengzhen Liu, William G Iacono, John K Hewitt, John E Hokanson, Kenneth Krauter, Markku Laakso, Kevin W Li, Sharon M Lutz, Matthew McGue, Anita Pandit, Gregory J M Zajac, Michael Boehnke, Goncalo R Abecasis, Scott I Vrieze, Xiaowei Zhan, Bibo Jiang, Dajiang J Liu
Meta-analysis of genetic association studies increases sample size and the power for mapping complex traits. Existing methods are mostly developed for datasets without missing values, i.e. the summary association statistics are measured for all variants in contributing studies. In practice, genotype imputation is not always effective. This may be the case when targeted genotyping/sequencing assays are used or when the un-typed genetic variant is rare. Therefore, contributed summary statistics often contain missing values...
July 17, 2018: PLoS Genetics
Paola Cusumano, Alberto Biscontin, Federica Sandrelli, Gabriella M Mazzotta, Claudia Tregnago, Cristiano De Pittà, Rodolfo Costa
Single microRNAs are usually associated with hundreds of putative target genes that can influence multiple phenotypic traits in Drosophila, ranging from development to behaviour. We investigated the function of Drosophila miR-210 in circadian behaviour by misexpressing it within circadian clock cells. Manipulation of miR-210 expression levels in the PDF (pigment dispersing factor) positive neurons affected the phase of locomotor activity, under both light-dark conditions and constant darkness. PER cyclical expression was not affected in clock neurons, however, when miR-210 was up-regulated, a dramatic alteration in the morphology of PDF ventral lateral neuron (LNv) arborisations was observed...
July 16, 2018: PLoS Genetics
Robert K Maeda, Jessica L Sitnik, Yohan Frei, Elodie Prince, Dragan Gligorov, Mariana F Wolfner, François Karch
Although thousands of long non-coding RNAs (lncRNA) have been identified in the genomes of higher eukaryotes, the precise function of most of them is still unclear. Here, we show that a >65 kb, male-specific, lncRNA, called male-specific abdominal (msa) is required for the development of the secondary cells of the Drosophila male accessory gland (AG). msa is transcribed from within the Drosophila bithorax complex and shares much of its sequence with another lncRNA, the iab-8 lncRNA, which is involved in the development of the central nervous system (CNS)...
July 16, 2018: PLoS Genetics
Sean M Cascarina, Kacy R Paul, Satoshi Machihara, Eric D Ross
Enhanced protein aggregation and/or impaired clearance of aggregates can lead to neurodegenerative disorders such as Alzheimer's Disease, Huntington's Disease, and prion diseases. Therefore, many protein quality control factors specialize in recognizing and degrading aggregation-prone proteins. Prions, which generally result from self-propagating protein aggregates, must therefore evade or outcompete these quality control systems in order to form and propagate in a cellular context. We developed a genetic screen in yeast that allowed us to explore the sequence features that promote degradation versus aggregation of a model glutamine/asparagine (Q/N)-rich prion domain from the yeast prion protein, Sup35, and two model glycine (G)-rich prion-like domains from the human proteins hnRNPA1 and hnRNPA2...
July 13, 2018: PLoS Genetics
Daniel F Rojas-Tapias, John D Helmann
Spx is a global transcriptional regulator present in low-GC Gram-positive bacteria, including the model bacterium Bacillus subtilis and various human pathogens. In B. subtilis, activation of Spx occurs in response to disulfide stress. We recently reported, however, that induction of Spx also occurs in response to cell wall stress, and that the molecular events that result in its activation under both stress conditions are mechanistically different. Here, we demonstrate that, in addition to up-regulation of spx transcription through the alternative sigma factor σM, full and timely activation of Spx-regulated genes by cell wall stress requires Spx stabilization by the anti-adaptor protein YirB...
July 12, 2018: PLoS Genetics
Lucia Carolina Leal-Esteban, Benjamin Rothé, Simon Fortier, Manuela Isenschmid, Daniel B Constam
Altered glucose and lipid metabolism fuel cystic growth in polycystic kidneys, but the cause of these perturbations is unclear. Renal cysts also associate with mutations in Bicaudal C1 (Bicc1) or in its self-polymerizing sterile alpha motif (SAM). Here, we found that Bicc1 maintains normoglycemia and the expression of the gluconeogenic enzymes FBP1 and PEPCK in kidneys. A proteomic screen revealed that Bicc1 interacts with the C-Terminal to Lis-Homology domain (CTLH) complex. Since the orthologous Gid complex in S...
July 11, 2018: PLoS Genetics
Delphine Dardalhon-Cuménal, Jérôme Deraze, Camille A Dupont, Valérie Ribeiro, Anne Coléno-Costes, Juliette Pouch, Stéphane Le Crom, Hélène Thomassin, Vincent Debat, Neel B Randsholt, Frédérique Peronnet
In Drosophila, ubiquitous expression of a short Cyclin G isoform generates extreme developmental noise estimated by fluctuating asymmetry (FA), providing a model to tackle developmental stability. This transcriptional cyclin interacts with chromatin regulators of the Enhancer of Trithorax and Polycomb (ETP) and Polycomb families. This led us to investigate the importance of these interactions in developmental stability. Deregulation of Cyclin G highlights an organ intrinsic control of developmental noise, linked to the ETP-interacting domain, and enhanced by mutations in genes encoding members of the Polycomb Repressive complexes PRC1 and PR-DUB...
July 11, 2018: PLoS Genetics
Mohammad Amin Omidbakhshfard, Ushio Fujikura, Justyna Jadwiga Olas, Gang-Ping Xue, Salma Balazadeh, Bernd Mueller-Roeber
Leaf growth is a complex process that involves the action of diverse transcription factors (TFs) and their downstream gene regulatory networks. In this study, we focus on the functional characterization of the Arabidopsis thaliana TF GROWTH-REGULATING FACTOR9 (GRF9) and demonstrate that it exerts its negative effect on leaf growth by activating expression of the bZIP TF OBP3-RESPONSIVE GENE 3 (ORG3). While grf9 knockout mutants produce bigger incipient leaf primordia at the shoot apex, rosette leaves and petals than the wild type, the sizes of those organs are reduced in plants overexpressing GRF9 (GRF9ox)...
July 9, 2018: PLoS Genetics
Vivek Iyer, Katharina Boroviak, Mark Thomas, Brendan Doe, Laura Riva, Edward Ryder, David J Adams
CRISPR-Cas9 technologies have transformed genome-editing of experimental organisms and have immense therapeutic potential. Despite significant advances in our understanding of the CRISPR-Cas9 system, concerns remain over the potential for off-target effects. Recent studies have addressed these concerns using whole-genome sequencing (WGS) of gene-edited embryos or animals to search for de novo mutations (DNMs), which may represent candidate changes introduced by poor editing fidelity. Critically, these studies used strain-matched, but not pedigree-matched controls and thus were unable to reliably distinguish generational or colony-related differences from true DNMs...
July 9, 2018: PLoS Genetics
Fabio Lino Gratani, Petra Horvatek, Tobias Geiger, Marina Borisova, Christoph Mayer, Iwan Grin, Samuel Wagner, Wieland Steinchen, Gert Bange, Ana Velic, Boris Maček, Christiane Wolz
The stringent response is characterized by (p)ppGpp synthesis resulting in repression of translation and reprogramming of the transcriptome. In Staphylococcus aureus, (p)ppGpp is synthesized by the long RSH (RelA/SpoT homolog) enzyme, RelSau or by one of the two short synthetases (RelP, RelQ). RSH enzymes are characterized by an N-terminal enzymatic domain bearing distinct motifs for (p)ppGpp synthetase or hydrolase activity and a C-terminal regulatory domain (CTD) containing conserved motifs (TGS, DC and ACT)...
July 9, 2018: PLoS Genetics
Caroline Choquet, Thi Hong Minh Nguyen, Pierre Sicard, Emeline Buttigieg, Thi Thom Tran, Frank Kober, Isabelle Varlet, Rachel Sturny, Mauro W Costa, Richard P Harvey, Catherine Nguyen, Pascal Rihet, Sylvain Richard, Monique Bernard, Robert G Kelly, Nathalie Lalevée, Lucile Miquerol
Left ventricular non-compaction (LVNC) is a rare cardiomyopathy associated with a hypertrabeculated phenotype and a large spectrum of symptoms. It is still unclear whether LVNC results from a defect of ventricular trabeculae development and the mechanistic basis that underlies the varying severity of this pathology is unknown. To investigate these issues, we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele...
July 6, 2018: PLoS Genetics
Pierre Baduel, Ben Hunter, Sarang Yeola, Kirsten Bomblies
Spatially structured plant populations with diverse adaptations provide powerful models to investigate evolution. Human-generated ruderal habitats are abundant and low-competition, but are challenging for plants not adapted to them. Ruderal habitats also sometimes form networked corridors (e.g. roadsides and railways) that allow rapid long-distance spread of successfully adapted variants. Here we use transcriptomic and genomic analyses, coupled with genetic mapping and transgenic follow-up, to understand the evolution of rapid cycling during adaptation to railway sites in autotetraploid Arabidopsis arenosa...
July 5, 2018: PLoS Genetics
Maxime Wery, Camille Gautier, Marc Descrimes, Mayuko Yoda, Valérie Migeot, Damien Hermand, Antonin Morillon
Antisense (as)lncRNAs can regulate gene expression but the underlying mechanisms and the different cofactors involved remain unclear. Using Native Elongating Transcript sequencing, here we show that stabilization of antisense Exo2-sensitivite lncRNAs (XUTs) results in the attenuation, at the nascent transcription level, of a subset of highly expressed genes displaying prominent promoter-proximal nucleosome depletion and histone acetylation. Mechanistic investigations on the catalase gene ctt1 revealed that its induction following oxidative stress is impaired in Exo2-deficient cells, correlating with the accumulation of an asXUT...
July 5, 2018: PLoS Genetics
Odelya H Kaufman, KathyAnn Lee, Manon Martin, Sophie Rothhämel, Florence L Marlow
The most prominent developmental regulators in oocytes are RNA-binding proteins (RNAbps) that assemble their targets into ribonucleoprotein granules where they are stored, transported and translationally regulated. RNA-binding protein of multiple splice forms 2, or Rbpms2, interacts with molecules that are essential to reproduction and egg patterning, including bucky ball, a key factor for Bb formation. Rbpms2 is localized to germ granules in primordial germ cells (PGCs) and to the Balbiani body (Bb) of oocytes, although the mechanisms regulating Rbpms2 localization to these structures are unknown...
July 5, 2018: PLoS Genetics
Xuguang Nie, Jinxuan Zheng, Christopher L Ricupero, Ling He, Kai Jiao, Jeremy J Mao
mTOR is a highly conserved serine/threonine protein kinase that is critical for diverse cellular processes in both developmental and physiological settings. mTOR interacts with a set of molecules including Raptor and Rictor to form two distinct functional complexes, namely the mTORC1 and mTORC2. Here, we used novel genetic models to investigate functions of the mTOR pathway for cranial neural crest cells (NCCs), which are a temporary type of cells arising from the ectoderm layer and migrate to the pharyngeal arches participating craniofacial development...
July 5, 2018: PLoS Genetics
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